Plasma cell tumors in humans most commonly occur as multiple myeloma, an incurable form of cancer. Biochemical lesions involved in the development of these tumors have been difficult to characterize and the most common biological association with this disease is an apparent critical role of Interleukin-6. Although IL-6 is one growth factor of importance in myeloma development, we have previously demonstrated a role for the Insulin-like growth factor receptor I (IGF-IR) signaling pathway in myeloma both in vitro and in vivo. Recent studies have focused on biochemical characterization of this signaling pathway. Stimulation with IGF-I ligand leads to activation of two cellular signaling cascades, the mitogen activated protein kinase (MAPK) and PI-3K pathways. Analysis of downstream elements in the PI-3K pathway revealed activation of Akt kinase leading to inhibition of processes causing normal cell death. Akt additionally activates GSK-3 beta and p70S6 kinase. A series of metabolic inhibitors have been used to determine the roles of these various elements in tumor cell proliferation and in crosstalk with other pathways. Inhibition of the MAPK pathway results in an approximate 20% decrease in proliferation whereas inhibition of the PI-3K pathway causes an 80% reduction in proliferation. Interestingly, inhibition of PI-3K also effects the MAPK pathway indicating crosstalk between these two cascades but only in one direction as inhibition of MAPK activity does not effect PI-3K. Inhibition of p70S6 kinase decreases proliferation ~ 40% and activation of this kinase is blocked by both MAPK and PI-3K inhibitors. These results indicate extensive cross talk between these two pathways and the mechanisms regulating such interactions are currently under investigation. Wnt proteins have been shown to be critical elements regulating development and inappropriate expression of Wnt's has been observed in human cancers. We have recently initiated studies to assess the potential role of Wnt's in myeloma. Exposure of myeloma cells to Wnt proteins results in striking morphological changes suggesting extensive rearrangement of the cytoskeleton. This morphological change is accompanied by activation of a classic Wnt signaling pathway resulting in stabilization of cellular beta catenin. Myeloma cells have been found to express mRNA encoding several different Wnt molecules as well as their cognate receptors (Frizzled proteins) indicating the potential for an autocrine signaling loop. Interestingly, similar expression could not be detected in B cell lymphomas representing an earlier stage in B cell differentiation. Current studies are in progress to biochemically characterize Wnt signaling in myeloma as well as the structural basis for the observed morphological changes. This project was formerly Z01 BC 05553-28 LG